Current Understanding of Leukocyte Phenotypic and Functional Modulation During Extracorporeal Membrane Oxygenation: A Narrative Review

Abstract

A plethora of leukocyte modulations have been reported in critically ill patients. Critical illnesses such as acute respiratory distress syndrome and cardiogenic shock, which potentially require extracorporeal membrane oxygenation (ECMO) support, are associated with changes in leukocyte numbers, phenotype, and functions. The changes observed in these illnesses could be compounded by exposure of blood to the non-endothelialized surfaces and non-physiological conditions of ECMO. This can result in further leukocyte activation, increased platelet-leukocyte interplay, pro-inflammatory and pro-coagulant state, alongside features of immunosuppression. However, the effects of ECMO on leukocytes, in particular their phenotypic and functional signatures, remain largely overlooked, including whether these changes have attributable mortality and morbidity. The aim of our narrative review is to highlight the importance of studying leukocyte signatures to better understand the development of complications associated with ECMO. Increased knowledge and appreciation of their probable role in ECMO-related adverse events may assist in guiding the design and establishment of targeted preventative actions.

Keywords: critically ill patients; extracorporeal membrane oxygenation; extracorporeal membrane oxygenation technology; innate and adaptive immunity; leukocyte modulation.

Figure 1

Summary of potential contributors to leukocyte modulation in critically ill ECMO patients.

Figure 2

The two “hit” ECMO model: Basic overview of early leukocyte modulation during extracorporeal membrane oxygenation (ECMO). 1^st hit: Immune modulation from the patient’s primary disease burden. 2^nd hit: The inflammatory response to ECMO is proposed to activate upon contact of blood with the non-endothelialized surface of the ECMO circuit and the non-physiological conditions generated. ECMO-mediated promotion of pro-inflammatory cytokines and chemokines, and other mediators (e.g. complement products) from non-physiological exposure, contact and cellular activation can lead to further activation of leukocyte subpopulations. During early ECMO, innate immune neutrophils and monocytes become the first to activate—consistently reported with an increased expression of surface integrins cluster differentiation (CD)11b and CD18. Alongside L-selectin (CD62L), these modulated integrin expressions potentiate an increase in leukocyte adhesion to the membrane oxygenator, as well as activated endothelium (e.g. increased Intercellular Adhesion Molecule (ICAM)-1) expression) and platelets [PLT; e.g. increased P-selectin glycoprotein ligand-1 (PSGL) and glycoprotein Ib alpha polypeptide (GIbα) expression]. As blood continues to circulate through the ECMO circuit: monocyte expression of tissue factor (CD142), neutrophil degranulation, neutrophil extracellular trap (NET)osis, pro-thrombogenic extracellular vesicle release and activation of downstream lymphocytes are also upregulated. All of which can contribute to the heightened systemic inflammatory response syndrome (SIRS), leukocytopenia, infection, end-organ damage, and thrombosis frequently reported in patients. (Figure created with BioRender.com).

Figure 3

Potential implications of documented leukocyte modulation in ECMO patient outcomes. human leukocyte antigen (HLA)-DR, tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-10, acute kidney injury (AKI), toll-like receptor (TLR)-4, lipopolysaccharides (LPS), von Willebrand factor (vWF) (Figure partially created with BioRender.com).